J Med Genet: first published as 10.1136/jmg.7.3.200 on 1 September 1970. Downloaded from

Journal of Medical Genetics (1970). 7, 200.

Tapeto-retinal Degenerations with Varying Clinical Features in Aland Islanders H. FORSIUS* and A. W. ERIKSSONt

During the period 1959-1962, we investigated pigmentosa reported in the literature show a great families afflicted with blindness in the Aland variety of clinical features (for references see archipelago, situated in the northern Baltic Sea be- Forsius and Eriksson, 1964a). tween Finland and Sweden. Among the natives of the Aland islands we observed various types of Kokar Pedigree (Families I-V) tapeto-retinal degeneration: Leber's congenital During 1960-1962 we examined almost all the perma- amaurosis, degeneratio retinae pigmentosa juvenilis, nent population of about 420 in the highly isolated island and retinitis punctata albescens. community of Kokar; in addition we examined many In 1969 we again surveyed the occurrence of poor who had emigrated and returned to Kokar on holidays. sight on the Aland islands, and found new cases of The total number of subjects examined was 565. dystrophic changes of the fundus in young subjects. On scanning the detailed and well-preserved church We also observed progression in some of the cases registers going back to the 1650's we found many persons we had on record. Some were with a record of night blindness, poor vision, or blind- patients also ness, often belonging to the same studied by (ERG), electro- sibship or closely re- lated in different ways. copyright. oculography(EOG), (ENG), As manifested in the Kokar families, the disease is anomaloscopy, the Farnsworth 100 Hue Test, characterized by night blindness, usually congenital, and , etc. relatively early impairment of vision, which may result in The question arose as to whether these clinically blindness at the age of 10-40 years. In the older age- different retinal abiotrophies of autosomal recessive groups, cases resembling atrophia gyrata were observed type could be due to the same mutant gene, causing (Fig. 1). We have interpreted the great diversity of a great diversity of clinical manifestations, depend- clinical forms of tapeto-retinal degeneration as variants of retinitis punctata albescens, and we believe that the ing partly on pleiotropy (polypheny) and partly on http://jmg.bmj.com/ the difference in age of the patients is one of the main progression of tapeto-retinal degeneration. causes of the differences in clinical picture (for details on This hypothesis was corroborated by the genea- pedigree, etc. see Forsius and Eriksson (1964a) and logical data. Many probands showing different Eriksson and Forsius (1964)). kinds of tapeto-retinal degeneration were found to have ancestors in common, particularly in the more Family I distant ascendancy, though some of them were born Agnes J.-R. Female, born in 1920, IV/4* children. in quite different parts of the Aland archipelago. Has always had night blindness. Reading vision lost at (Water excluded, this archipelago comprises 1505 the age of 36. In 1963, visual acuity in both 0-1 on September 29, 2021 by guest. Protected sq. km., water included about 6,000 sq. km., and the (-1-0 D). Fundus degenerated, obvious choroidal distance sclerosis. ERG extinct. Diagnosis: degeneratio tapeto- between some of the inhabited islands is as retinalis of the type gyrata (Fig. 1). much as 100 km.) A brother (Arnold, J.) became blind at the age of Furthermore it seemed unlikely that the small about 38, a sister (Astrid, J.) at the age of 10-12 years. population of Aland (about 21,000 subjects) would The latter shows Turner's syndrome: 45,X/46,XX show so many different recessively inherited mosaicism (de la Chapelle, 1962; Case 15, p. 58). tapeto-retinal diseases, which are all rare, both in Sweden and in Finland. It should be borne in Family H mind that the atypical forms of degeneratio retinae Gunnevi F. Female, born in 1945, I/1 child, birth- weight 2490 g. Hearing somewhat impaired, probably as a result of bilateral * Address: Department of , University of Oulu, middle inflammation at the age Hospital, Uusikatu 50, Oulu, Finland. of 7-8. Has shown a squint since birth. On ophthal- t Address: Folkhalsan Institute of Genetics, Tologatan 12, mological examination for squinting, changes of the Helsinki 10, Finland. * IV/4 etc., means 4 h born of 4 sibs. 200 J Med Genet: first published as 10.1136/jmg.7.3.200 on 1 September 1970. Downloaded from

Tapeto-retinal Degenerations with Varying Clinical Features in Aland Islanders 201 copyright.

FIG. 1. Family I (Agnes J.-R.) Left eye of 42-year-old woman with hemeralopia, showing degeneration of the fundus resembling atrophia chorioidea gyrata. ERG extinct. fundus were observed. State in 1969: V. o.dx. 1-25 Visual fields normal. Colour vision: secondary dys- (-3-5 D). V. o.sin. 1-2 (-0 5 D). Fundus: pale chromatopsia varying in type. ERG: b-wave normal. papillae, normal blood vessels. Everywhere in the Diagnosis: retinitis punctata albescens. fundus were abundant small pigment spots. Dark A sister (Inga S.) was diagnosed by Dr. M. Zewi as a adaptation (Goldmann-Weekers), normal in both eyes. case of retinitis punctata albescens. Another sister http://jmg.bmj.com/ Diagnosis: atrophia nervi optici, degeneratio retinae (Carola S. born in 1957) had also shown night blindness pseudopigmentosa ? since infancy. State in 1968 (Dr. Zewi): V. o.dx. 0-2 (cyl +3*0 D ax 90°). V. o.sin. 025 (cyl +3-0 D ax Family m 1000). Abundant small light spots in the equatorial Anna L.-L. Female, born 1883, II/5 children. region of the fundus. Diagnosis: retinitis punctata Investigated in 1959 (she died soon afterwards), showed albescens. polar cataract and pronounced choroidal sclerosis and bone cell pigments in the totally destroyed fundus. Family V on September 29, 2021 by guest. Protected Vision 1/oc, no light projection. Diagnosis: final pic- Agnes E.-N. Female, born in 1900. Parents ture of tapeto-retinal degeneration. closely related. A sister (Anna E.), diagnosed by us as a case of , became blind at the age of Family IV 47 years. V. o.dx. 10 (-1F25 Dcyl -0-25 ax 90°). Yngve S. Male, bom in 1947, III/4 children. Somewhat narrow retinal blood vessels. V. o.sin. 1J0 Examined by us in 1962 and 1967. No definite pro- (-1*75 D). Somewhat narrow blood vessels. Drusen gression. Has always shown poor night vision. Slight papilla. Sector-shaped choroidal sclerosis with bone- subjective impairment of vision during the past few cell like pigments temporally of the fovea, extending to years. V. o.dx. 1-2 (+ 10 Dcyl-3-75 ax 6°). V. o.sin. the periphery. Visual field defect in this area. After 60 0-9 (+ 1-25 Dcyl -3-5 ax 3°). Fundus: papillae some- minutes of dark adaptation the final light threshold of what prominent, pale. Except at the outermost peri- both eyes was about 104 utpL, which is about 1 log unit phery and the central area, abundant small white spots poorer than normal. Subnormal ERG. (The case has in the fundus, and abundant very small pigmented areas been previously described by Elenius, Forsius, and in the (Fig. 2). Fovea and blood vessels normal. Eriksson 1961.) Diagnosis: degeneratio retinae et chori- Dark adaptation much impaired (Goldmann-Weekers). oideae o.sin. Drusen papilla o.sin. simplex o.a. J Med Genet: first published as 10.1136/jmg.7.3.200 on 1 September 1970. Downloaded from

2")02 Forsius and Eriksson Carl Johan L. Male, bom in 1948, I/6 children. Just managed reading at elementary school up to the age of 12, after which he visited a school for the blind. No subjective night blindness. State in 1959: V. o.dx. finger counting in front of the eyes (+ 70 D). V. o.sin. hand movements (+6-0 Dcyl +1-0 ax 900). Fundus yellow papillae, narrow blood vessels. Abundant bone- cell like pigments peripherally and round ones centrally. Rapid jerky . Diagnosis: amaurosis congenita (Leber). Birgitta L. Female, bom in 1953, V/6 children. Poor sight since birth, continuously impaired. Has always shown night blindness. State in 1969: vision (1959 and 1969) in both eyes finger counting 0 5 m. (+ 6-0 Dcyl + 40 ax 90°). Central visual field lacking. Papilla pale, swollen-'drusen papilla'. Narrow blood vessels. Very heavy bone-cell pigmentation extending to the periphery. Dark adaptation much impaired (105_106 puL Goldmann-Weekers). ENG: ocular nystagmus. Diagnosis: amaurosis congenita (Leber). Bern L. Male, bom in 1956, VI/6 children. Im- pairment of vision was observed before he was 1 year old. Vision problems particularly in the dusk. State in 1963: V. o.dx. finger counting 3 m. (+ 8-0 Dcyl + 2-5 FIG. 2. Family IV (Yngve S.) Male, 20, with retinitis punctata ax 90°). V. o.sin. finger counting 20 cm. (+2-0 Dcyl albescens. Abundant white spots superficially in the retina and + 2-0 ax 90°). Reddish-yellowish papillae, narrow small pigment particles in the deep layers. arteries, normal veins. All over the fundus, but least in the macular region, pigment spots and streaks, some Main Island Pedigree (Families VI-X) the shape of bone cells. Abundant small white or yellow copyright. spots peripherally in the retina. State in 1969: V. o.a. Family VI. According to the parents, the affected hand movements. Fundus: pale atrophic papillae, subjects showed relatively normal vision up to the age narrow blood vessels in the superficial retinal layer. of 2-4 years, when obvious impairment in the form of Fluorescein angiography revealed total atrophy of the 'near-sightedness' set in. The three sibs described be- retinal pigment layer. Adaptation much impaired (105 low have all visited a school for the blind in Helsinki. ppL, Goldmann-Weekers). ENG: ocular nystagmus. Diagnosis: amaurosis congenita (Leber).

Family VII http://jmg.bmj.com/ Dorrit M. Female, bom in 1955, I/2 children. Night vision always poor. State in 1969: V. o.a. 5/50. Re- fraction: +4-0 Dcyl + 1-0 ax 90° o.dx. +4 0 Dcyl + 1-5 ax 90° o.sin. Fundus: narrow blood vessels. Pale yellow papillae. Centrally in the fundus choroid vessels clearly visible. Choroid shines through especi- ally on fluorescein angiography. Peripherally the retina shows milky degeneration with occasional bone-cell on September 29, 2021 by guest. Protected pigments. Some white-greyish spots in the central portion of the periphery (Fig. 3). Adaptation impaired 1 log unit (Goldmann-Weekers). Obvious secondary dyschromatopsia. ENG: latent nystagmus of a type suggesting a lesion of the cerebellum. Vision and fundus appearance in 1963 and 1969 about the same. Diagnosis: late form of amaurosis congenita (Leber) ? Family VIII Gunnel P. Female, born in 1937, I/2 (II/3). Parents are cousins of fourth degree and related to Families VI FIG. 3. Family VII (Dorrit M.) Female, 14. Large central and VII. Dizygotic twin, the other twin, a girl, died at retinal degeneration with round pigment spots in both eyes. Narrow the age of 17 days. Birthweight 1500 g. Convulsive blood vessels, pale yellow papillae. Peripherally some white- greyish spots and occasional bone-cell pigments. Diagnosis: late fits during the first 2-3 weeks of life and at the age of 3j form of amaurosis congenita (Leber) ? years. At the age of 27 years an attack of epileptic J Med Genet: first published as 10.1136/jmg.7.3.200 on 1 September 1970. Downloaded from

Tapeto-retinal Degenerations with Varying Clinical Features in Aland Islanders 203 grand mal. EEG: suggestive of frontal brain lesion. Foglo-SottungaPedigree (Families XIII-XVII) Normal development of speech; started walking at the Family XIII age of 4. Has visited a school for the blind. Shows mental retardation and weakness of the left Dailis P.-L. Female, born in 1930, IV/4 children. extremities. Became aware of of In 1959, vision in both eyes finger counting 0 5-1 m. impairment vision at the age of 22. (+ 2-0 D). Ocular nystagmus. Fundus: An ophthalmologist noted haemorrhages in the retina. papillae State in 1969: V. o.dx. finger counting 3 m (-3-25 D). white, pale, borderlines sharp; blood vessels normal; V. o.sin. 0-2 retina normal. Diagnosis: atrophia nervi optici secun- (-4-75 Dcyl + 1-25 ax 900). Centrally in daria. the fundus there was obvious atrophy of the retina and choroid; occasional retinal pigment spots visible at the outermost periphery, though the severity of the changes Family IX steadily decreased towards the periphery. Some pig- Elmar 0. Male, born in 1934, I/7 children. Blind ment was seen along the retinal blood vessels. The since birth. In 1969 vision o.a. 0. Central corneal visual field showed a large central defect. Adaptation opacities and keratoconus in both eyes. Pale yellowish much impaired (by two log units), EOG subnormal, papillae, very narrow vessels. Obvious choroidal ERG subnormal (Fig. 4). sclerosis. Scanty bone-cell pigmentation all over the When this patient was first examined by us in 1963, fundus. Ocular nystagmus. Diagnosis: amaurosis con- vision was 0-25 on both eyes. There was an atrophic genita (Leber). area of the same size as in 1969, but the margin of the degeneration had peculiar semitranslucent vascularized Family X grey foci, which were the size of the papillae, and clearly Jack C. Male, born in 1962, II/2 children. Blind raised from the remainder of the retina (Fig. 5a). These since birth. Nystagmus observed at the age of 2 pseudotumours were still visible in 1969, though they months. From time to time he rubs his eyes frantically. were less prominent than previously (Fig. 5b). New State in 1969: vision in both eyes 1/ oo. Mature cataract large choroidal blood vessels were seen. We have not in right eye. Posterior capsular opacity in left eye. seen published reports of such pseudotumours. For Fundus: pale papilla, narrow arteries, no pathological fluorescein angiographic findings see Fig. 5c. Occa- pigmentation. Keratoconus with central corneal opa- sional white-yellowish spots were seen near the margin cities in both eyes. Diagnosis: amaurosis congenita of the focus. We have noted haemorrhages only once (Leber). (Fig. 5a). Diagnosis: degeneratio retinae et chorioideae copyright. centralis. Kumlinge Pedigree (Families XI-XII) Family XIV Family XI Anni Paulina L. Female, born in 1898, VII/9 Fjalar H. Male, born in 1915, IV/7 children (the children. Subjectively, she has not been night blind. proband's eldest sister was bom with only locomotor In 1968 abalatio retinae was seen in the left eye, with vision; died of 'Spanish disease' at the age of 13). numerous peripheral ruptures in a very atrophic retina. Parents were cousins of second degree in two different http://jmg.bmj.com/ ways. Congenital night blindness. Vision poor al- 0-6- D.L. 39years ready before school age. State in 1969: V. o.dx. 1/oo 1 left eye (-0-25 Dcyl -0-5 ax 90°). V. o.sin. 1/cc (-0-25 Dcyl 0 5 b wave +0-75 ax 0c). Lens clear. ENG: latent nystagmus. Irregular pendular deviations with eyes open suggestive 04- of ocular nystagmus. Extremely pale papillae and x narrow blood vessels. Obvious choroidal atrophy. -J-j

> on September 29, 2021 by guest. Protected Diagnosis: amaurosis congenita (Leber). E 0-3- 0

Family XII 0 2 - Fanny E. Female, born in 1900, VII/8 children. a wave Parents were cousins of second degree. She and the mother in Family XI are cousins. The patient and her youngest sister showed endogenous depression at times. Had night blindness and poor vision as long as she could 0 -l 0 remember, but when she was 20 could still read with the -3 -2 -I ° aid of a magnifying glass. State in 1969: V. o.dx. 1/cc Relative light intensity (-2-25 D). V. o.sin. 0 (+0-25 Dcyl +1-25 ax 90°). FIG. 4. Family XIII (Dailis P.-L.) Female, born in 1930. ERG Ocular nystagmus. Cataracta polaris posterior. of left eye, recorded with a Techronix 502A oscilloscope. Before Atro- examination the patient spent half an hour in the dark. After phic papillae, abundant bone-cell pigmentation. Marked coupling the electrodes the eye was exposed to a total of 10 steadily choroidal sclerosis. Diagnosis: degeneratio retinae strengthened flashes at about 1-minute intervals. Maximum value pigmentosa juvenilis. Late form of amaurosis congenita of b-wave 0 9 mV. The curves show the growth of the b- and a- waves with increasing stimulation. ERG is within the normal (Leber). range. J Med Genet: first published as 10.1136/jmg.7.3.200 on 1 September 1970. Downloaded from

204 Forsius and Eriksson copyright. http://jmg.bmj.com/

FIG. 5. (Dailis P.-L.) Female, born in 1930, with degeneratio retinae and chorioideae centralis (and see opp.) 5a. Left eye on 17 September 1963. Extensive choroidal sclerosis. Normal retinal blood vessels. Haemorrhage in papilla (arrow). Grey, raised semitranslucent pseudotumour, the size of the papilla, medially at the border to the normal tissue (arrow), showing large choroidal vessels. on September 29, 2021 by guest. Protected

Normal vision in the right eye. One year later pro- The abdomen was swollen, and there was frequent gressive haemorrhagic was seen flatulence and vomiting. The patient died at the age of covering a large proportion of the central fundus and 3j months. Tissue preparations were subjected to surrounded by white exudate. V. o.dx. 0-25. Treated thorough lipid chemical investigations and were also at the University Eye Hospital, Turku. Diagnosis: submitted to Prof. H. F. Thannhauser, Boston. These degeneratio maculae senilis haemorrhagica o.dx. Ablatio studies as well as patho-anatomical investigations per- retinae totalis o.sin. formed by Dr. L. Meurman, were clearly indicative of Gaucher's infantile lipidosis. Family XV The parents of these patients and two living sibs were Gerhard L. Male, born in 1953, birthweight 2680 g. examined by us in 1969: they were ophthalmologically Admitted to hospital because of vomiting and poor normal. general condition at the age of 6 weeks. Died at the age of 3 months. Diagnosis: Gaucher's infantile lipidosis. Family XVI Gertrud L. Female, born in 1955, birthweight Bengt T. Male, born in 1951, I/4. Poor vision was 3080 g. Admitted to hospital for loose mucous stools. observed at the age of 10 on examination performed in J Med Genet: first published as 10.1136/jmg.7.3.200 on 1 September 1970. Downloaded from

Tapeto-retinal Degenerations with Varying Clinical Features in Aland Islanders 205 school, and since then there has been gradual impair- ment. Night vision always satisfactory. State in 1969: V. o.dx. finger counting 3 m. V. o.sin. 01. Emmetropia. Centrally in the fundus an area the size of the papilla, in which the retinal pigment epithelium is destroyed and the choroid shines through (Fig. 6). Occasional pig- ments along the blood vessels in the equatorial region. In an area at a distance from the fovea equal to the dia- meter of the papilla, numerous grey spots seen in the

5b. Detail of grey pseudotumour laterally of the macular region in 5c. Same area as in Fig. 5b on 25 April 1969. The pseudotumour the right eye (September 17, 1963). From 19 January 1963, to 25 is much less prominent than six years earlier. Many of the choroidal

February 1964, the pseudotumour showed no photographic changes. vessels have disappeared and new vessels have developed. copyright. http://jmg.bmj.com/ on September 29, 2021 by guest. Protected

5d. Same area as in Fig. 5b and c, on 25 April 1969. Fluorescein 5e. Same area as in Fig. 5b, c, and d, 18 seconds later than in 5d. angiography in initial phase. Retinal artery only weakly filled, Centrally, a large choroidal blood vessel, not filled during whereas the dilated choroidal blood vessels in the pseudotumour are angiography, appears dark against the light background. This obviously filled. Choroidal sclerosis, especially to the right. vessel, which is seen below in Fig. 5c, was lacking in 1963-1964. J Med Genet: first published as 10.1136/jmg.7.3.200 on 1 September 1970. Downloaded from

206 Forsius and Eriksson deep layers of the retina. Normal visual fields. EOG subnormal. Dark adaptation: one log unit poorer than normal. ERG normal; maximum of the b-wave 0 7 mV, maximum of the a-wave 0-2 mV. Obvious secon- dary dyschromatopsia predominantly in the tritan axis (Farnsworth panel D-15 test). Anomaloscopic equa- tion in the protanomal direction. Diagnosis: degene- ratio retinae centralis; Stargardt's macular dystrophia ? Borje T. Male, born in 1954, II/4 children. Poor sight noted at the age of 6. Has passed elementary school. Night vision always satisfactory. State in 1969: V. o.dx. 0-1 (-0-25 Dcyl +05 ax 90O). V. o.sin. 0-15 (-0 75 Dcyl + 1-25 ax 900). Centrally in the fundus a dystrophic focus, in which the choroidal vessels shine through in an area with a cross-section of 1- papillary diameter (Fig. 7a). Under the vascular layer in the retina, about one papillary diameter outside this area and extending to the equator, there are whitish- grey spots, hardly distinguishable from the surrounding tissue. Centrally the pigment in the deep retinal layers is disintegrated into spots. Above the pigment layer, a strongly light-reflecting layer is seen. Fluorescein angiography clearly showed that the pigment defect area in the retina was larger than shown by (Fig. 7b). Adaptation (Goldmann-Weekers): one log unit poorer than normal. Visual field peripherally nor- mal EOG subnormal. ERG within the normal range Maximum of the b-wave 0-5 mV, maximum of the a- 20 FIG. 6. (Bengt T.) Male, 18. Fluorescein angiography copyright. seconds after the dye has reached the retina. Retinal pigment also wave 0-2 mV. Diagnosis: degeneratio retinae centralis; injured outside the macular region. Stargardt's dystrophy ? http://jmg.bmj.com/ on September 29, 2021 by guest. Protected

(a) (b) FIG. 7. (Borje T.) Male, 15. (a) Foveal area in a patient with central chorioretinal atrophy. The five dark spots are marks for stereogrammetric analysis. (b) Same eye as in Fig. 7a. Fluorescein angiography in initial venous phase. Pigment epithelium also injured outside the central area. J Med Genet: first published as 10.1136/jmg.7.3.200 on 1 September 1970. Downloaded from

Tapeto-retinal Degenerations with Varying Clinical Features in A4land Islanders 207 Family XVH (e.g. Guglianetti, 1950). This is in good agreement Nandor G. Male, bom in 1906, has experienced with our clinical findings in Families XVI and IV. vision problems in the dusk and dark since childhood. These two families come from the communities of Became totally blind in less than a week at the age of 48. Foglo-Sottunga and Kokar, respectively, which are State in 1959: V. o.a. finger counting 1 m. No nystag- both situated in the south-eastern part of the Aland mus. Pupils react to light. Snow-white papillae with archipelago. However, genealogical studies cover- sharp borders. Narrow blood vessels. Diagnosis: ing the last 200-300 years did not reveal any blind atrophia nervi optici l.a. ancestors in common (Fig. 8-10). The white spots in retinitis punctata albescens and Discussion fundus albipunctata disappear with advancing age Many reports have been published on the occur- (Franceschetti, 1953). This may perhaps explain rence of various forms of degeneration of the fundus the variations in our findings in related families in within the same pedigree or even the same family the Kokar isolate. On the other hand, to the best unit. Choroidal sclerosis and retinitis punctata of our knowledge no case of typical retinitis punc- albescens have been observed in the same family tata albescens (as observed, for instance, in Family

I MAIN ISLAND * Amaurosis congenita (Leber) ) Deqeneratio tapetoretinalis im + Atrophia nervi optici t Died as infant b Investigated

III t Index cases 6 No symptoms of defective vision known in descendant F Family

IV copyright. http://jmg.bmj.com/ on September 29, 2021 by guest. Protected

*1955 * 1945

FIG. 8. Part of the pedigree of the subjects from the Aland main island showing tapeto-retinal degeneration. Third from left, genera- tion VII, Family XIII, is identical with twelfth, generation VII, in the Foglo-Sottunga pedigree (Fig. 10). The first subject from the left (born in 1734) in generation V in Family VII moved with her husband from Kumlinge to the Aland main island in the middle of the 1770's. She is the sister of one of the ancestors in Family XII in the Kumlinge pedigree (fourth from left, generation V). The proband in Family II is also found in the Kokar pedigree (Forsius and Eriksson, 1964a). Her ancestor in the main island pedigree-ninth from left, generation VII-was a pilot who moved from Kokar to the northern part of the main island during the latter half of the 18th century. J Med Genet: first published as 10.1136/jmg.7.3.200 on 1 September 1970. Downloaded from

208 Forsius and Eriksson

.4 KUMLINGE -01- * Amourosis congenita (Leber) D Defective vision B61 Blind at 16 Consanguinity t2 Died at 2 2 Investigated f Index cases F Family

0: C)cr 0:

0 c z Cl)

-

c4 copyright. http://jmg.bmj.com/

FIG. 9. Part of the pedigree of the subjects from the island commune of Kumlinge showing tapeto-retinal degeneration. The connexions to the Foglo-Sottunga families are shown to the right (cf. text and key to Fig. 8 and 10). Cases in the ascendancy, which, according to official records, e.g. parish registers, have poor sight, are indicated by thick circles (o).

IV) has been described in families with Leber's con- of 10-15 years (Families VI, VII, XI, and XII). on September 29, 2021 by guest. Protected genital amaurosis. It has been suggested that the The resemblance of the fundus pictures shown by anlage of tapeto-retinal degeneration manifests the children in Families VI and VII is remarkable. itself in the form of retinitis pigmentosa in dark Keratoconus has been observed in Leber's (heavily pigmented) subjects, and in the form of amaurosis in as much as 38 6% of the cases (Karel, retinitis punctata albescens in fair individuals 1968). On the Aland islands only 2 of 23 patients (Milner, 1932). Our findings do not contradict with definite pigmentary retinopathy had kerato- this theory, but it should be borne in mind that conus. Whitish-grey spots in the periphery are retinitis punctata albescens has been reported in often seen in this disease (Waardenburg, 1957; black people (Albert and Geltzer, 1969). Alstrom and Olson, 1957). In the present series In our families, Leber's congenital blindness several patients showed grey spots in the equatorial occurs in two forms: the congenitally blind type region. Somewhat larger and less conspicuous with nystagmus (Families IX and X), and a some- spots were observed in the brothers of Family XVI. what milder form with central degeneration in The history and clinical picture of the subjects with which vision is present to some degree up to the age Leber's congenital amaurosis differed considerably J Med Genet: first published as 10.1136/jmg.7.3.200 on 1 September 1970. Downloaded from

Tapeto-retinal Degenerations with Varying Clinical Features in Aland Islanders 209

I FOGLO6-SOTTUNGA ODegeneratio retinae centralis gLipidosis (M.GAUCHER INFANT) *Atrophia nervi optici OIInvestigated II ®No symptoms of defective vision known inaescendant B Blind III BoBlind as infant t2 Died at two years of age t Died as infant Consanguinity IV a Index cases F Family

V

VI

VII

VIII

Ix copyright. x

XI

Xii

- http://jmg.bmj.com/ + I +`I -1903 v

FIG. 10. Part of the pedigree of the subjects from the neighbouring island communes of Foglo and Sottunga showing tapeto-retinal degeneration. The pedigree shows the close relation between Family XV, in which infantile lipidosis was observed, and the families having central retinal degeneration. The connexions to the Kumlinge pedigree are shown to the left (cf. text and key to Fig. 8 and 9). Cases in the ascendancy, which, according to official records, e.g., parish registers, have poor sight, are indicated by thick circles (o). from the fundus findings in Families XIII and XVI. Bamatter, Franceschetti, and Klein, 1961; Francois In both cases the central retino-choroidal sclerosis and De Rouck, 1961) and in central choroidal scle- was the feature. The predominant EOG, ERG, rosis (Francois and De Rouck, 1961). All these on September 29, 2021 by guest. Protected and adaptation were found to be relatively normal patients were, however, young. in Family XVI, in which the first symptom was ob- With regard to the patients showing atrophic served at school age or somewhat later, and the changes of the fundus classification is difficult. In clinical picture resembled most that described in Family II it seems possible that viral degeneratio atrophia chorioidea centralis, a disease occurring in retinae pigmentosa is involved, whereas in Family a recessively inherited form (Waardenburg, 1952), or VIII the condition may be due to cerebral injury in the related Stargardt's dystrophy, which has also caused by prematurity or infection (meningitis ?). been described as recessively inherited (Francois However, considering the kinship between these and Verriest, 1956). We have also considered the individuals and the families showing tapeto-retinal possibility of Sorsby's inflammatory dystrophy, degeneration, the possibility cannot be excluded which has likewise been described in a recessive that these two cases and the case in Family XVII form (Sorsby, 1940; Sorsby and Mason, 1949). represent deviating formes frustes or heterozygotic In occasional cases a normal ERG has been ob- manifestations of the same mutant gene. served in Leber's disease (Alstr6m and Olson, 1957; Ammann and Marty (1962) described a large 2 J Med Genet: first published as 10.1136/jmg.7.3.200 on 1 September 1970. Downloaded from

210 Forsius and Eriksson pedigree from a Swiss Alpine isolate showing various retinitis pigmentosa and congenital tapeto-retinal clinical manifestations, e.g. fundus albipunctatus (a amaurosis (Leber) occurring in the same family: in stationary form of retinitis punctata albescens), this instance 3 of the 24 maternities were twin pairs. degeneratio retinae pigmentosa atypica, degeneratio Emigration to the outer Aland archipelago be- maculae senilis, and central dystrophy ofthe fundus. gan about 700 years ago, chiefly from the main Tapeto-retinal degeneration occurs in association island. It seems probable that these island popu- with congenital disorders of sphingolipid meta- lations are descended from a small number of im- bolism. In pedigrees with Niemann-Pick's disease migrants, who moreover may have been related to and Tay-Sachs' disease, tapeto-retinal degeneration each other. Owing to the hardships of daily life has been encountered (Hanhart, 1956; Fraser and in these communities there has been little migration Friedmann, 1967). Degenerative retinal changes to them later. This is true in particular for the last have also been noted in patients with the infantile few centuries. The part played by founder effect form of Gaucher's disease (Eyb, 1952). Hence, the and isolation in the Aland archipelago is corro- concurrence of Gaucher's infantile lipidosis and borated by the fact that neighbouring insular com- tapeto-retinal degeneration in the Foglo-Sottunga munities show extreme gene frequencies deviating pedigree is not perhaps accidental. Gaucher's very much from each other (Eriksson and Forsius, disease is rare. Only 300 cases have been reported 1964). (Hsia, Naylor, and Bigler, 1962), even including the Provided that there were among the first immi- Jewish cases. grants some subjects with a recessive mutant gene In regard to the degenerations of the fundus seen not involving any significant handicap in hetero- in the pedigrees described in this study a classi- zygous form, the smallness of the original popula- fication into the following variants seems justified: tion (founder effect) and the isolation, perhaps in (1) a variant corresponding to Leber's congenital connexion with random genetic drift, would account amaurosis, and (2) a variant manifesting itself as for a high frequency of this gene, notwithstanding retinitis punctata albescens or as central atrophic the growth of the population. degeneration of the fundus, just as in the pedigree When the relationship between two relatives in a copyright. described by Ammann and Marty (1962) (cf. also large panmixed population becomes remote, the Fraser and Friedmann, 1967). probability that they share a common gene (identi- With the above-mentioned two sibs with cal by descent) becomes very small. However, Gaucher's infantile lipidosis and two cases of typical inhabitants in small isolates have often, particularly ocular nerve atrophy excluded (Families VIII and in earlier generations, so many common ancestors XVII), a total of 23 cases of definite degeneration of that their marriages may well be compared to the fundus was thus diagnosed in 14 families in the marriages between cousins in a panmixed popula- Aland archipelago in 1959-1969. tion. Consequently, marriage partners in small iso- http://jmg.bmj.com/ The tapeto-retinal degeneration occurring on the lated populations are quite likely to have genes in Aland islands does not seem to be combined with common. Therefore, the probability that the off- disorders of a neurological or psychiatric nature. spring will be homozygous is much greater, as dicta- Impaired hearing was observed in two ofthe affected ted by chance. The heavy accumulation ofblindness subjects (Families I and II), but this was probably and poor sight in the pedigrees in the outer Aland due to otitis media. No accumulation of deafness archipelago is evidence in favour of the above hypo- or deaf-muteness was observed in the pedigrees of theses, considering in particular that trachoma has on September 29, 2021 by guest. Protected the probands. With the exception of the proband not been reported in these communities, and that we in Family VIII, who showed prematurity, epilepsy, have not observed any accumulation of severe and mental retardation, the patients studied, as well myopia or juvenile cataract or glaucoma. The as their families, showed at least normal intelligence. cases of defective vision detected among the ances- Hormonal disturbances were only observed in a case tors or their sibs are therefore helpful from the of Turner's syndrome (Family I). Tests for standpoint of tracing the path of the mutant gene in toxoplasmosis and syphilis were negative in all the pedigrees. investigated cases. Twin births occurred in 6 of 15 It may be suggested that the different clinical families showing abiotrophies. However, con- manifestations are due to one and the same gene sidering the scantiness of the series, this must be mutation. In an equally large panmixed popula- attributed to chance and to the fact that the fre- tion this would mean a gene frequency of about quency of twin births has been relatively high on the 0 034. On the assumption that both parents of the Aland islands (Eriksson, 1964). Ammann, Klein, affected subjects are heterozygotes, another estimate and Franceschetti (1965) reported typical cases of of the gene frequency is obtained. Apart from the J Med Genet: first published as 10.1136/jmg.7.3.200 on 1 September 1970. Downloaded from

Tapeto-retinal Degenerations with Varying Clinical Features in Aland Islanders 211 14 families with definite tapeto-retinal degeneration approach to the study of rare hereditary diseases. discovered, there may be others in which both When a large population is screened for vision parents are heterozygotes, though the defect allele defects, for instance, the sample is selective and has not manifested itself in any of the children. severe cases are predominant. Provided that the Presuming full penetrance of the monogenic re- total population of an isolate is examined, a more cessive autosomal gene, there ought to be further exact picture is obtained of penetrance and pheno- 9-2 parent pairs with this mutant gene. If these typic expression (e.g. formesfrustes, degree of mani- 23-2 families are compared to the total number of festation among heterozygotes) as well as of the age married couples with at least one child living on of manifestation, the progression, etc. of the defect Aland during the period 1881-1960 (totalling about involved. In various ways these factors may be sug- 8000), a gene frequency of 0-027 is obtained. Not- gestive of genetic differences, as in cases of tapeto- withstanding the simplified premises, the two retinal degeneration, though the latter may be due methods of estimation give gene frequencies which to the same mutant gene. Follow-up studies of in any event are of the same order. The above- affected families and more thorough and extensive mentioned gene frequencies for Aland are 5-7 times investigations of isolates may contribute significantly higher than these obtained by Alstrom and Olson to a more adequate classification of the tapeto- (1957) for Sweden, and about 8 times higher than retinal degenerations and to a better understanding those obtained for the regions bordering on Aland, of their associations with other affections. i.e. the counties of Stockholm and Uppsala. It is noteworthy, however, that in Sweden the highest Summary gene frequency (0-011) was obtained for the island Families in the Aland archipelago showing of Gotland. There is historical evidence of in- tapeto-retinal degeneration varying in type are tensive contracts between the Swedish-speaking described. Subjects coming from the same district populations on Aland and Gotland, in particular and in some instances from the same pedigree during and after the time of the Vikings (Dreijer, showed different retinal Leber's 1960). abiotrophies: congenital amaurosis with or without keratoconus, copyright. On the assumption that the different clinical mani- atrophia chorioideae centralis, senile macular de- festations are due to three different mutations in generation with haemorrhages, retinitis punctata different loci, the total gene frequency would be albescens, atrophia nervi optici, and Gaucher's much higher, i.e. 0 055. Even when the isolate infantile lipidosis. The majority of the cases were effect with consanguineous marriages etc. is taken investigated using Goldmann-Weeker's adapto- into account, it seems very unlikely that several meter, fluorescein angiography, ERG, EOG, ENG, tapeto-retinal diseases, which are exceedingly rare in etc. Genealogical studies of the pedigrees of the areas bordering on Aland, would occur in this archi- probands covering the past 200-300 years revealed http://jmg.bmj.com/ pelago independently of each other, and that all many ancestors in common. In 11 of the 16 would exhibit such high frequencies of manifesta- families studied, the parents were cousins of 1st to tion. 4th The that the Of those admitted to a school for the blind in degree. possibility very variable Sweden, 10% showed heredoretinopathia congeni- clinical pictures of tapeto-retinal degeneration talis (Alstrom and Olson, 1957). In our series from shown by Aland islanders are caused by the same Aland, no less than 60% of the subjects who mutation is discussed. on September 29, 2021 by guest. Protected showed poor sight or blindness when young be- We are greatly indebted to Dr. A. G. M. van Vliet, longed to families with tapeto-retinal degeneration. Rotterdam, for the nystagmographic investigations, to Among 16 patients not showing autosomal recessive Dr. P. Tuomaala, Oulu, Finland, for the ERG and EOG tapeto-retinal degeneration, 7 males had the X investigations, to J. Fellman, M.Sc., Helsinki, for statistical consultations, and to Mr. H. Nieminen, Oulu, chromosomal Aland eye syndrome (Forsius and for the clinical photographs. Eriksson, 1964b; Waardenburg, Eriksson, and These studies were suported by grants from the Forsius, 1967; Eriksson, Waardenburg, and Forsius, National Institute of Health, Public Health Service 1969). Irrespective of whether the number of sub- (NB-06368-02), Bethesda; the Association for the Aid of Crippled Children, New York; the Sigrid Juselius jects with tapeto-retinal degeneration is compared Foundation; and the Finnish Council for Medical to the total population or to the number of indi- Science. viduals showing other types of blindness, the fre- quency of tapeto-retinal degeneration on Aland is REFERENCES very high. Albert, D. M., and Geltzer, A. I. (1969). Retinitis punctata albescens in a negro child studied with fluorescein angiography. The investigation of isolates offers a useful Archives of Ophthalmology, 81, 170-176. J Med Genet: first published as 10.1136/jmg.7.3.200 on 1 September 1970. Downloaded from

212 Forsius and Eriksson

Alstrom, C. H., and Olson, 0. (1957). Heredo-retinopathia con- punctata albescens, constatee 54 ans auparavant. Ophthalmo- genitalis monohybrida recessiva autosomalis. Hereditas, 43, 1-178. logica, 125, 340-341. Ammann, F., Klein, D., and Franceschetti, A. (1965). Genetic and Franqois, J., and De Rouck, A. (1961). Degenerescence tapeto- epidemiological investigations on pigmentary degeneration of retinienne congenitale de Leber. In 18e Congres de l'Association the retina and allied disorders in Switzerland. Journal of the de Pediatrie de Langue franfais, Geneve, 1961. p. 68. Karger, Neurological Sciences, 2, 183-196. Basle.

-, and Marty, F. (1962). Une grande famille Valaisanne avec -, and Verriest, G. (1956). La detection a l'aide des tests de plusieurs branches atteintes de formes differentes de degene- Farnsworth des dyschromatopsies acquisies dans les degeneres- rescence tapeto-retinienne remontant au meme couple ancestral. cences tapeto-retiniennes. Bulletin de la Societe belge d'Ophtal- Journal de Ginitique Huwnaine, 11, 221-231. mologie, 113, 381-398. Bamatter, F., Franceschetti, A., and Klein, D. (1961). Aspects Fraser, G. R., and Friedmann, A. I. (1967). The Causes ofBlindness cliniques, ophtalmologiques et gdn6tiques des abiotrophies neuro- in Childhood. A Study of 766 Children with Severe VisualHandicaps. retiniennes en pediatrie. Bibliotheca Paediatrica, 76, 1-120. The Johns Hopkins Press, Baltimore. de la Chapelle, A. (1962). Cytogenetical and clinical observations Guglianetti, L. (1950). Sur la sclerose generalisee des vaisseaux in female gonadal dysgenesis. Acta Endocrinologica, Suppl. 65. choroidiens d'origine familiale. In Acta XVI Concilium Ophtal- Dreijer, M. (1960). Hauptlinge, Kaufleute und Missionare im Nor- mologicum Britannia, Vol, 1 493-497. British Medical Association, den vor tausendJ7ahren, p. 311. Skr. Alands Kulturstiftelse, Mar- London. iehamn. Hanhart, E. (1956). Die Schweizer Falle von Splenohepatome- Elenius, V., Forsius, H., and Eriksson, A. W. galie (Niemann-Pick). Ein Beitrag zur genetischen Abgrenzung (1961). Subnormal der Acta electroretinograms in a case of tapetoretinal degeneration com- Phosphatid-Lipoidosen. Geneticae Medicae et Gemello- bined with drusen of the optic disc and glaucoma simplex. Acta logiae, 5, 294-315. Ophthalmologica, 39, 343-351. Hsia, D. Y.-Y., Naylor, J., and Bigler, J. A. (1962). The genetic Eriksson, A. W. (1964). Pituitary gonadotrophin and mechanism of Gaucher's disease. In Cerebral Sphingolipidoses. dizygotic A on twinning. Lancet, 2, 1298-1299. Symposium Tay-Sachs Disease and Allied Disorders, p. 327. Ed. by S. M. Aronson and B. W. Volk. Academic Press, New -. and Forsius, H. (1964). Studies on human population York and London. genetics and anthropology in isolates on the Aland Islands. J3ournal de Ginetique Karel, I. (1968). Keratoconus in congenital diffuse tapetoretinal Humaine, 13, 60-75. degeneration. Ophthalmologica, 155, 8-15. -, Waardenburg, P. J., and Forsius, H. (1969). X-linked Miner, J. G. (1932). Retinitis pigmentosa and retinitis punctata hereditary Aland eye disease. Paper read for European Society albescens. of Ophthalmology, for Human Genetics, Liverpool meeting, 19-20 April, 1969. British-Journal 16,418-421. Bulletin of the Sorsby, A. (1940). The dystrophies of the macula. British Journal European Society for Human Genetics, 3, 77-81. of Ophthalmology, 24, 469-529. Eyb, Ch. (1952). Augenhintergrund-Veranderungen bei der kind- -, and Mason, M. E. A fundus with lichen Gaucher'schen Erkrankung. Wiener klinische Wochen- J. (1949). dystrophy unusual features. (Late onset and dominant inheritance of a central schrift, 64, 38. retinal lesion showing oedema, haemorrhage and exudates develop- Forsius, H., and Eriksson, A. W. (1964a). Differents aspects ing into generalised choroidal atrophy with massive pigment copyright. ophtalmoscopiques de la degenerescence tapeto-retinienne chez proliferation.) British_Journal of Ophthalmology, 33,67-97. les habitants d'un archipel. Ophthalmologica, 147, 40-56. Waardenburg, P. J. (1952). Angio-sclerose familiale de la choroide. -, and - (1964b). Ein neues Augensyndrom mit x-chromo- Journal de Ginitique Humaine, 1, 83-88. somaler Transmission. Eine Sippe mit Fundusalbinismus, (1957). Does or Foveahypoplasie, agenesis dysgenesis neuroepithelialis retinae, Nystagmus, Myopie, Astigmatismus und whether or not related to keratoglobus, exist ? Ophthalmologica, Dyschromatopsie. Klinische Monatsblatter fur Augenheilkunde, 454-460. 144, 447-457. 133, -, Eriksson, A. W., and Forsius, H. (1967). Aland eye disease Franceschetti, A. (1953). Degenerescence chorioretinienne fami- (Syndroma Forsius-Eriksson). Progress in Neuro-ophthalmology liale avec angiosclerose choroidienne, stade tardif d'une retinitis 2, 336-339. http://jmg.bmj.com/ on September 29, 2021 by guest. Protected